Tumor suppressive role of mir‐342‐5p in human chondrosarcoma cells and 3d organoids

Abstract

Chondrosarcomas are malignant bone tumors. Their abundant cartilage‐like extracellular matrix and their hypoxic microenvironment contribute to their resistance to chemotherapy and ra-diotherapy, and no effective therapy is currently available. MicroRNAs (miRNAs) may be an inter-esting alternative in the development of therapeutic options. Here, for the first time in chondrosar-coma cells, we carried out high‐throughput functional screening using impedancemetry, and identified five miRNAs with potential antiproliferative or chemosensitive effects on SW1353 chondro-sarcoma cells. The cytotoxic effects of miR‐342‐5p and miR‐491‐5p were confirmed on three chon-drosarcoma cell lines, using functional validation under normoxia and hypoxia. Both miRNAs induced apoptosis and miR‐342‐5p also induced autophagy. Western blots and luciferase reporter assays identified for the first time Bcl‐2 as a direct target of miR‐342‐5p, and also Bcl‐xL as a direct target of both miR‐342‐5p and miR‐491‐5p in chondrosarcoma cells. MiR‐491‐5p also inhibited EGFR expression. Finally, only miR‐342‐5p induced cell death on a relevant 3D chondrosarcoma organoid model under hypoxia that mimics the in vivo microenvironment. Altogether, our results revealed the tumor suppressive activity of miR‐342‐5p, and to a lesser extent of miR‐491‐5p, on chondrosarcoma lines. Through this study, we also confirmed the potential of Bcl‐2 family members as therapeutic targets in chondrosarcomas.